Postural Tachycardia Syndrome (POTS) is a debilitating clinical condition characterized by intolerance to upright posture of at least 6 months duration, associated with consistent orthostatic tachycardia of at least 30 bpm, and with orthostatic symptoms relieved by lying down. POTS is primarily a disorder of women (4-5 fold incidence over men) with predisposition for younger individuals, often of child-bearing age. We and others have found that patients with POTS have significantly diminished health-related quality of life, to levels comparable to patients with congestive heart failure or chronic obstructive pulmonary disease. While grossly elevated heart rates are the hallmark physiologic findings in POTS, there are several other important physiological abnormalities. We have found low plasma volume in the majority of patients with POTS. This can trigger the sympathetic activation that drives the tachycardia. The exact cause of the hypovolemia has not been elucidated, but our preliminary studies indicate that aldosterone levels are paradoxically diminished, and this likely contributes to the low blood volume. Quite surprisingly in light of the low aldosterone and blood volume, angiotensin II levels were elevated in patients with POTS. These data suggest a decreased adrenal sensitivity to angiotensin II in patients with POTS. Perturbations in the Angiotensin-Aldosterone Axis may play a critical role in the pathophysiology of POTS. Our preliminary studies also indicate that patients with POTS have an impaired ability to retain sodium at times of stress or depletion. In addition to an inadequate level of circulating aldosterone in POTS, there could be diminished renal sensitivity to mineralocorticoid stimulation in these patients. Given the low plasma volume in many patients with POTS, a common strategy in their management is to ask patients to follow a high sodium diet, in an effort to increase their plasma volume. Unfortunately, there are no published data demonstrating that this simple strategy is effective in this patient population. Our overarching hypothesis is that problems in aldosterone and sodium handling lead to reduced plasma volume and that these factors play an important role in the pathophysiology of POTS. To the test these hypotheses we propose the following Specific Aims: 1. To test the hypothesis that in patients with POTS that AT1 Receptor mediated aldosterone release is blunted. 2. To determine the anti-natriuretic response to aldosterone in patients with POTS. 3. To test the hypothesis that patients with POTS have a blunted (inadequate) plasma volume expansion in response to a high sodium diet. 4. To test the hypothesis that chronic mineralocorticoid stimulation can restore blood volume in POTS. PUBLIC HEALTH RELEVANCE: Postural tachycardia syndrome (POTS), or chronic orthostatic intolerance, is a disorder that typically afflicts female of child-bearing age, causes significant functional disability, and results in a very poor quality of life. Underlying this condition in many patients is a poorly understood chronic hypovolemia (low blood volume) which may be due to problems in the way these patients regulate their sodium intake and excretion. If we can mechanistically understand the regulation and effects of the hormones that control sodium handling in POTS, we can then develop rational treatment approaches to improve heart rate control and decreased the disability in POTS.